1. Field of the Invention
The invention provides a novel class of cyclic compounds, pharmaceutical compositions comprising such cyclic compounds and methods of using such compounds to treat or prevent diseases and disorders associated with cyclin-dependent kinases (CDKs) activity, particularly diseases associated with the activity of CDK2 and CDK5.
2. Background
The cyclin-dependent protein kinases (CDKs) are a group of serine/threonine kinases (STKs) that control the progression of cells through the cell cycle. Cyclins are small regulatory proteins that act by binding to and activating CDKs that then trigger various phases of the cell cycle by phosphorylating and activating selected proteins involved in the mitotic process. In addition to the binding of cyclin, CDK activation requires the phosphorylation of a specific threonine residue and the dephosphorylation of a specific tyrosine residue. CDK2 is essential for normal cell cycling and plays a critical role in disorders arising from abnormal cell cycling, a common characteristic of many oncological disorders. Inhibitors of CDK2 are therefore useful for the treatment of various types of proliferative diseases such as cancer and other diseases or conditions associated with abnormal cell growth.
CDK5, unlike other CDKs, is not involved in cell cycle progression control and is not activated upon association with a cyclin. CDK5 is active in neuronal cells upon association with a 35 kD protein (p35) or a proteolytic fragment of p35(p25). Under physiological conditions, CDK5 is involved in neuron development and, under pathological conditions, CDK5 is responsible for the hyperphosphorylation of the microtubule associated protein, tau. CDK5 also phosphorylates dopamine and cyclic APM-regulated Phosphorprotein (DARPP-32) at threonine 75 and is thus indicated in having a role in dopaminergic neurotransmission. Consequently, CDK5 along with its cofactor p35 or p25 has been linked to neurodegenerative disorders and inhibitors of CDK/p35 or CDK5/p25 are therefore useful for the treatment of neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, Huntington's disease or stroke.
Therefore, the novel compounds of this invention are useful in the therapy of proliferative diseases such as cancer, inflammation, arthritis, cardiovascular disease and neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, stroke, or Huntington's disease. These compounds also are useful in the treatment of topical and systemic fungal infections.